Hepatitis B virus, which can cause acute and/or persistent/progressive chronic diseases, belongs to the family of hepatic viruses. Hepatitis B virus can also cause many other clinical manifestations in pathological morphology, especially chronic inflammation of the liver, cirrhosis of the liver, and carcinogenesis of hepatocytes. In addition, its co-infection with hepatitis D leads to an adverse effect during the development of the disease.
Conventional agents that are approved for the treatment of chronic hepatitis are interferon and lamivudine. However, interferon has only moderate activity but high toxic side effects; although lamivudine has good activity, its drug resistance increases rapidly during the treatment and the rebound effect often occurs after stopping treatment. Lamivudine (3-TC) has an IC50 value of 300 nM (Science, 299 (2003), 893-896).
Deres et al. reports dihydropyrimidine (HAP) compounds substituted by a heteroaryl ring, represented by Bay41-4109 and Bay39-5493, which are capable of inhibiting HBV replication by preventing the formation of normal nucleocapsids. Bay41-4109 exhibited good drug metabolism parameters in clinical studies (Science, 299 (2003), 893-896). Studies on its mechanism of action revealed that dihydropyrimidine compounds substituted by a heteroaryl ring change the angle between the dimers forming the nucleocapsid by acting on the 113-143 amino acid residues of the core protein, resulting in the formation of unstable expanded nucleocapsid and the acceleration of core protein degradation (Biochem. Pharmacol., 66 (2003), 2273-2279). In addition, the patent application WO2015180631 also discloses compounds as HBV inhibitors. Currently, there is still a need to develop new compounds which can be effectively used as antiviral drugs, especially drugs for the treatment and/or prevention of hepatitis B and especially drug crystalline forms with improved stability, hygroscopicity and efficacy, which are more suitable for forming drugs, thereby achieving good effects in the pharmaceutical manufacturing and drug application stages.